The invention relates to a new process for the preparation of 4-(4-pyridinyl)benzoic acid, or a salt thereof.
4-(4-Pyridinyl)benzoic acid, sodium salt (CAS registry number 207798-97-8), is useful as an intermediate in the synthesis of 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine disclosed as Example 7 in PCT publication WO9821188. A number of references describe the preparation of 4-(4-pyridinyl)benzoic acid. For example, a process is described in WO9821188, Example 4, where the intermediate is made using a three stage process involving a palladium-mediated biaryl Suzuki coupling as the key step as shown in Scheme 1. 
We have surprisingly found that 4-carboxybenzeneboronic acid and 4-bromopyridine hydrochloride may be directly coupled together, in high yield, without the need to protect the carboxylic acid functionality, as shown in Scheme 2. 
Therefore, in a first aspect the invention is a process for the preparation of 4-(4-pyridinyl)benzoic acid, or a salt thereof, comprising reacting a mixture of 4-carboxybenzeneboronic acid, optionally in the form of a salt, and 4-bromopyridine, also optionally in the form of a salt, particularly the hydrochloride salt, in the presence of base and a catalyst, all reactants being substantially dissolved in a solvent.
To carry out the reaction, the mixture may be heated. Particularly, the mixture may be heated to reflux.
Catalysts suitable for use in the process are, for example, Ni and particularly, Pd(0) or Pd(II) based catalysts. Specific and preferred catalysts are those described herein.
Bases suitable for the use in the invented process may be weak or strong and are advantageously selected on the basis of being soluble in the solvent used. Certain strong bases may be less suitable as they may promote proto-deboronation of the boronic acid. The presence of this adverse reaction may be determined simply by detecting the formation of benzoic acid, such as, for example by the use of HPLC. The nature of the proto-deboronation reaction, and how to avoid it, are described in Thomas I. Wallow and Bruce M. Novak J. Org. Chem. 1994, 59, 5034-5037, and references cited therein. Specific and preferred bases are described herein.
Solvents suitable for use in the reaction are selected for an ability to solubilise the intermediates and the base. Suitable solvents include aqueous and organic solvents, or mixtures of either or both. Particular solvents are aqueous, protic and dipolar aprotic solvents or mixtures thereof Specific and preferred solvents are described herein.
It has been found that using the process of the Invention, 4,4xe2x80x2-biphenyldicarboxylic acid (CAS registry number 787-70-2) of Formula I, a homo-coupled impurity of the 4-carboxybenzeneboronic acid intermediate may be formed. 
Once present, this impurity is difficult to reduce to levels acceptable for the manufacture of pharmaceuticals. However, the yield of 4-(4-pyridinyl)benzoic acid has been improved and the level of the homo-coupled impurity reduced by using an appropriate catalyst, base and solvent system in the invented process.
Accordingly, a second aspect of the invention is a process that can be scaled up for large scale manufacture of 4-(4-pyridinyl)benzoic acid in a yield of 90% (w/w) or more whilst controlling the level of the homo-coupled impurity to less than 2% (w/w), and usually less than 0.5% (w/w).
This aspect of the Invention is a process for the preparation of 4-(4-pyridinyl)benzoic acid, or a salt thereof, comprising reacting 4-carboxybenzoic acid, optionally in the form of a salt, with 4-bromopyridine, optionally in the form of a salt, and with a base all reactants being dissolved in a solvent, particularly aqueous ethanol, and in the presence of catalyst (R3P)4Pd catalyst, wherein R is an aromatic or heteroaromatic ring, cyclic alkyl or aliphatic group. Particularly R is phenyl.
This process provides material of acceptable organic purity for use in the manufacture of pharmaceuticals. However, the level of residual palladium catalyst may be high, for example greater than 500 ppm, according to pharmaceutical standards. Accordingly, a number of different process modifications were investigated to reduce the amount of catalyst residue in the isolated material. Such modifications included ligand exchange, base treatment, adsorption onto solid supports and liquid-liquid extraction. Of these liquid-liquid extraction showed the most promise on a small scale but was found to be unreliable on scale-up.
An alternative approach to minimising the catalyst residue was therefore investigated. This involved the use of a water soluble palladium catalyst. Examples of such catalysts are described in the literature. For example, Christian Amatore, Errol Blart, Jean Pierre Genet, Anny Jutand, Sandrine Lemaire-Adoire, and Monique Savignac. J. Org. Chem. 1995, 60, 6829-6839, describe the preparation from palladium acetate and the trisodium salt of 3,3xe2x80x2,3xe2x80x3-phosphinidyne-tris(benzenesulphonic acid).
Therefore, a third aspect of the Invention is a process for the manufacture of 4-(4-pyridinyl)benzoic acid, or a salt thereof, comprising reacting 4-carboxybenzeneboronic acid, optionally in the form of a salt, with 4-bromopyridine, optionally in the form of a salt, and with a base all parts being substantially dissolved in a solvent and in the presence of a water soluble Pd(0) based catalyst.
Particularly, in this aspect of the Invention the Pd(0) catalyst is formed in situ, by mixing a Pd(U)species, such as palladium acetate, with a ligand, such as 3,3xe2x80x2,3xe2x80x3-phosphinidyne-tris(benzenesulphonic acid)trisodium salt, in a suitable solvent.
The following non-limiting examples illustrate the invention.